Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma

Summary

ALK-positive anaplastic large cell lymphoma (ALCL) represents a subset of non-Hodgkin’s lymphoma that is treated with crizotinib, a dual ALK/MET inhibitor. Despite the remarkable initial response, ALCLs eventually develop resistance to crizotinib. ALK inhibitor resistance in tumors is a complex and heterogeneous process with multiple underlying mechanisms, including ALK gene amplification, ALK kinase domain mutation, and the activation of various bypass signaling pathways. To overcome resistance, multiple promising next-generation ALK kinase inhibitors and rational combinatorial strategies are being developed. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired crizotinib resistance by exposing a highly sensitive NPM-ALK-positive ALCL cell line to increasing doses of crizotinib until resistance emerged. We found that the NPM-ALK mutation was selected under intermediate-concentration drug stress in resistant clones, accompanied by activation of the IGF-1R pathway. In the crizotinib-resistant ALCL cell model, the IGF-1R pathway was activated, and combined ALK/IGF-1R inhibition improved therapeutic efficacy. Furthermore, we also detected the NPM-ALK G1269A mutation, which had previously been demonstrated to result in decreased affinity for crizotinib, in the resistant cell model. Although crizotinib was ineffective against cells harboring the NPM-ALK G1269A mutation, five structurally different ALK inhibitors, alectinib, ceritinib, TAE684, ASP3026 and AP26113, maintained activity against the resistant cells. Thus, we have shown that second-generation ALK tyrosine kinase inhibitors or IGF-1R inhibitors are effective in treating crizotinib-resistant tumors.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81372532), and the Science and Technology Planning Project of Liaoning Province of China (No. 201800449), and the scientific research foundation for the introduction of talents, Liaoning Cancer Hospital & Institute (No. Z1702). The authors report no conflicts of interest in this work.

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Correspondence to Yunpeng Liu or Jingdong Zhang.

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Li, Y., Wang, K., Song, N. et al. Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma. Invest New Drugs 38, 599–609 (2020). https://doi.org/10.1007/s10637-019-00802-7

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Keywords

  • ALK
  • ALCL
  • Crizotinib
  • IGF-1R
  • Drug resistance